In the United States, about 1 in 8 women in the Unites States will develop invasive breast cancer over the course of her lifetime. Triple negative breast cancer (TNBC) accounts for ~15-20% of all breast cancer incidences. They are highly aggressive, malignant, and with the worst prognosis among all types of breast cancers. Despite the fact that targeted therapies have become the first-line treatment for many different types of cancers, no targeted therapy is now available for TNBC. Chemotherapy is the current mainstay of treatment for TNBC. Besides severe side effects associated with chemotherapies, the selection pressure induced by nonspecific chemo drugs and development of drug resistance can promote metastasis. A targeted therapy will revolutionize treatment regimens for TNBC patient by replacing interventions that have life-threatening toxicities. Among all genetic alternations, the tumor suppressor TP53 gene (encoding p53) is inactivated by mutation or deletion in 60-88% of TNBCs. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment. In 67.2% of TNBCs containing partial TP53 deletion, we identified a drug target gene, POLR2A that is co-deleted with TP53. Inhibiting POLR2A with small compound drug ?-Amanitin selectively inhibits proliferation, survival and tumorigenic potential of TNBC cells with partial loss of the TP53 gene. Previous clinical applications of ?-Amanitin have been limited due to its liver toxicity. We found that ?-Amanitin-based antibody drug conjugates (ADCs) are highly effective therapeutic agents with significantly reduced toxicity. In this proposal, we will use Cetuximab, a monoclonal antibody specific for TNBCs, to develop ?-Amanitin-based ADCs. We propose that ?-Amanitin-conjugated Cetuximab is a specific and effective drug for TNBC treatment. Successful development of this project will revolutionize treatment regimens for TNBC patient by replacing interventions that have life-threatening toxicities with novel antibody- drug conjugates that are safe and effective.